PLEKHM1

Summary

PLEKHM1 (pleckstrin homology and RUN domain containing M1, HGNC:29017) is a protein-coding gene on chromosome 17q21.31, encoding Pleckstrin homology domain-containing family M member 1 (Q9Y4G2). Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. It is a selective cancer dependency (DepMap: 23.3% of cell lines).

The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 9842 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive osteopetrosis 6 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 196 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 39
• Cancer dependency (DepMap): dependent in 23.3% of screened cell lines
• MANE Select transcript: NM_014798

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29017
Approved symbol	PLEKHM1
Name	pleckstrin homology and RUN domain containing M1
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0356
Ensembl gene	ENSG00000225190
Ensembl biotype	protein_coding
OMIM	611466
Entrez	9842

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 11 protein_coding, 11 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000430334, ENST00000446609, ENST00000579131, ENST00000579197, ENST00000580205, ENST00000580404, ENST00000581448, ENST00000582119, ENST00000583150, ENST00000584420, ENST00000585506, ENST00000586084, ENST00000586562, ENST00000589780, ENST00000590991, ENST00000591580, ENST00000700123, ENST00000700124, ENST00000700125, ENST00000700126, ENST00000700127, ENST00000700128, ENST00000700129, ENST00000700130, ENST00000700131, ENST00000700132, ENST00000700133, ENST00000861476, ENST00000958646, ENST00000958647

RefSeq mRNA: 2 — MANE Select: NM_014798 NM_001352825, NM_014798

CCDS: CCDS32671, CCDS92344

Canonical transcript exons

ENST00000430334 — 12 exons

Exon	Start	End
ENSE00002396912	45477900	45478147
ENSE00002728455	45435900	45437969
ENSE00002732949	45490652	45490721
ENSE00003467291	45475100	45475726
ENSE00003502650	45440163	45440226
ENSE00003502845	45468209	45468593
ENSE00003527104	45445470	45445663
ENSE00003555588	45453355	45454272
ENSE00003613178	45439477	45439634
ENSE00003626074	45482437	45482525
ENSE00003663683	45458169	45458439
ENSE00003684428	45450618	45450763

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.07.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5170 / max 14.8748, expressed in 235 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
166550	0.4094	188
166549	0.1076	44

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.07	gold quality
esophagus mucosa	UBERON:0002469	95.91	gold quality
blood	UBERON:0000178	95.62	gold quality
bone marrow	UBERON:0002371	93.08	gold quality
bone marrow cell	CL:0002092	92.93	gold quality
skin of leg	UBERON:0001511	92.68	gold quality
vagina	UBERON:0000996	92.65	gold quality
minor salivary gland	UBERON:0001830	92.26	gold quality
esophagus	UBERON:0001043	92.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.98	gold quality
sural nerve	UBERON:0015488	91.98	gold quality
granulocyte	CL:0000094	91.85	gold quality
zone of skin	UBERON:0000014	91.84	gold quality
cerebellum	UBERON:0002037	91.62	gold quality
cerebellar hemisphere	UBERON:0002245	91.60	gold quality
cerebellar cortex	UBERON:0002129	91.57	gold quality
ectocervix	UBERON:0012249	91.41	gold quality
saliva-secreting gland	UBERON:0001044	91.35	gold quality
monocyte	CL:0000576	91.15	gold quality
leukocyte	CL:0000738	91.12	gold quality
skin of abdomen	UBERON:0001416	90.58	gold quality
apex of heart	UBERON:0002098	90.47	gold quality
uterine cervix	UBERON:0000002	90.43	gold quality
mucosa of transverse colon	UBERON:0004991	90.22	gold quality
spleen	UBERON:0002106	90.08	gold quality
upper lobe of left lung	UBERON:0008952	90.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.72	gold quality
pituitary gland	UBERON:0000007	89.70	gold quality
adenohypophysis	UBERON:0002196	89.63	gold quality
right lobe of thyroid gland	UBERON:0001119	89.55	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting PLEKHM1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-12119	99.87	68.35	1653

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• These data indicate that B2 is a novel, ubiquitously expressed protein with a putative adapter function. The protein has been named AP162. (PMID:12820725)
• PLEKHM1 is a novel gene implicated in the development of osteopetrosis, with a putative critical function in vesicular transport in the osteoclast. (PMID:17404618)
• heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts (PMID:17997709)
• Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain; this interaction is critical for their function; show Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase (PMID:20943950)
• PLEKHM1 regulates autophagosome-lysosome fusion through homotypic fusion and protein sorting complex and LC3/GABARAP proteins. (PMID:25498145)
• Authors show that Pleckstrin homology domain-containing protein family member 1 (PLEKHM1), a lysosomal adaptor, is targeted by Salmonella through direct interaction with SifA. (PMID:25500191)
• identified PLEKHM1 as an endolysosomal adaptor platform that acts as a central hub to integrate endocytic and autophagic pathways at the lysosome (PMID:25905573)
• The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways. (PMID:33452816)
• Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking. (PMID:35981699)
• Downregulation of MYBL1 in endothelial cells contributes to atherosclerosis by repressing PLEKHM1-inducing autophagy. (PMID:38797732)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plekhm1	ENSDARG00000099954
mus_musculus	Plekhm1	ENSMUSG00000034247
rattus_norvegicus	Plekhm1	ENSRNOG00000028521
drosophila_melanogaster	Plekhm1	FBGN0034694
caenorhabditis_elegans		WBGENE00013093

Paralogs (4): RUBCNL (ENSG00000102445), DEF8 (ENSG00000140995), RUBCN (ENSG00000145016), PLEKHM3 (ENSG00000178385)

Protein

Protein identifiers

Pleckstrin homology domain-containing family M member 1 — Q9Y4G2 (reviewed: Q9Y4G2)

Alternative names: 162 kDa adapter protein

All UniProt accessions (15): Q9Y4G2, A0A8V8TPC1, A0A8V8TPC5, A0A8V8TPW0, A0A8V8TPW4, A0A8V8TQN1, A0A8V8TQZ6, A0A8V8TQZ8, J3KRL8, J3KRU0, J3KS30, K7EII8, K7EMP2, K7EPF2, K7EQ68

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Acts as a dual effector of RAB7A and ARL8B that simultaneously binds these GTPases, bringing about clustering and fusion of late endosomes and lysosomes. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Interaction with Arl8b is a crucial factor in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts. May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7. May have a role in sialyl-lex-mediated transduction of apoptotic signals. Involved in bone resorption. (Microbial infection) In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7.

Subunit / interactions. Interacts (via N- and C-terminus) with RAB7A (GTP-bound form). Simultaneously interacts with RAB7A and ARL8B; bringing about clustering and fusion of late endosomes and lysosomes. Interacts (via RUN domain) with ARL8B (GTP-bound form); the interaction is required for PLEKHM1 localization to lysosomes and for ARL8B function in delivery and degradation of endocytic and autophagic cargo in lysosomes. PLEKHM1 and PLEKHM2 compete for interaction with ARL8B. Interacts with ARL8A; the interaction is weaker than with ARL8B. Interacts with VPS41, VPS11, VPS18, VPS33A and VPS39; indicative for an association with the HOPS complex; the interactions with, at least, VPS41, VPS11, VPS18 and VPS33A require ARL8B. Interacts with GABARAP, GABARAPL, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C. Interacts with PAFAH1B. Interacts (via N- and C-terminus) with NDEL1. Interacts (via C-terminus) with MAP3K7. Interacts (via N- and C-terminus) with FAM98A. Interacts (via C-terminus) with DEF8; this interaction is weak but increased in a RAB7A-dependent manner. In colon carcinoma and breast carcinoma cells, it interacts with sialyl-lex-positive protein. (Microbial infection) Interacts with Salmonella typhimurium sifA.

Subcellular location. Autolysosome membrane. Endosome membrane. Late endosome membrane. Lysosome membrane.

Tissue specificity. Expressed in placenta, liver, prostate, thymus, spleen, ovary, colon, colon carcinoma and peripheral blood lymphocytes (PBL). Weakly expressed in brain, lung, kidney, and testis. No expression in heart, skeletal muscle, pancreas and small intestine. Predominantly expressed in the breast carcinoma cell line MCF-7.

Disease relevance. Osteopetrosis, autosomal recessive 6 (OPTB6) [MIM:611497] A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. The disease is caused by variants affecting the gene represented in this entry. Osteopetrosis, autosomal dominant 3 (OPTA3) [MIM:618107] A form of osteopetrosis, a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and an autosomal dominant form occurring in adolescence or adulthood. OPTA3 is characterized by typical features of osteopetrosis such as fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in bone mineral density. Some patients exhibit localized osteosclerosis and generalized osteopenia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins GABARAP, GABARAPL, GABARAPL2, and LC3A/B/C.

Miscellaneous. Sialyl-lex is a carcinoma associated antigen.

RefSeq proteins (2): NP_001339754, NP_055613* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR004012	Run_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR025258	RH_dom	Domain
IPR037213	Run_dom_sf	Homologous_superfamily
IPR042827	PLEKHM1_PH	Domain
IPR047326	RUN_PLEKHM1	Domain
IPR051366	DEF8	Family

Pfam: PF02759, PF13901

UniProt features (31 total): mutagenesis site 10, region of interest 5, modified residue 4, domain 3, sequence variant 2, sequence conflict 2, chain 1, short sequence motif 1, compositionally biased region 1, strand 1, zinc finger region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5DPS	X-RAY DIFFRACTION	2
8JC5	X-RAY DIFFRACTION	2.01
5DPW	X-RAY DIFFRACTION	2.19
5DPR	X-RAY DIFFRACTION	2.5
5DPT	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4G2-F1	66.86	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 219, 432, 435, 490

Mutagenesis-validated functional residues (10):

Position	Phenotype
60	strongly reduces interaction with arl8b. no effect on interaction with rab7a. no effect on late endosome and lysosome cl
63	no effect on interaction with arl8b. no effect on interaction with rab7a.
119–123	reduces interaction with arl8b. no effect on interaction with rab7a. loss of interaction with arl8b as well as late endo
720–722	disrupts interaction with rab7a.
729	disrupts interaction with rab7a.
769	disrupts interaction with rab7a.
1021	disrupts interaction with rab7 and no localization to endososmal membranes; when associated with g-1024, l-1029 and g-10
1024	disrupts interaction with rab7 and no localization to endososmal membranes; when associated with g-1021, l-1029 and g-10
1029	disrupts interaction with rab7 and no localization to endososmal membranes; when associated with g-1021, g-1024 and g-10
1032	disrupts interaction with rab7and no localization to endososmal membranes; when associated with g-1021, g-1024 and l-102

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 258 (showing top): GOBP_LYSOSOMAL_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, SP3_Q3, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_RUFFLE_ASSEMBLY, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, AAAYRNCTG_UNKNOWN, GOBP_MACROAUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_ORGANELLE_MEMBRANE_FUSION

GO Biological Process (7): protein transport (GO:0015031), lysosome localization (GO:0032418), positive regulation of bone resorption (GO:0045780), autophagosome-lysosome fusion (GO:0061909), positive regulation of ruffle assembly (GO:1900029), late endosome to lysosome transport (GO:1902774), autophagy (GO:0006914)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleoplasm (GO:0005654), nucleolus (GO:0005730), lysosome (GO:0005764), late endosome membrane (GO:0031902), autolysosome (GO:0044754), autolysosome membrane (GO:0120281), lysosomal membrane (GO:0005765), endosome (GO:0005768), endosome membrane (GO:0010008), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	2
cellular anatomical structure	2
transport	1
intracellular protein localization	1
establishment of protein localization	1
vacuolar localization	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
vesicle fusion	1
macroautophagy	1
ruffle assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of ruffle assembly	1
lysosomal transport	1
intercellular transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membraneless organelle	1
lytic vacuole	1
late endosome	1
endosome membrane	1
secondary lysosome	1
lysosomal membrane	1
autolysosome	1
lysosome	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEKHM1	GABARAP	O95166	948
PLEKHM1	OSTM1	Q86WC4	919
PLEKHM1	CLCN7	P51798	908
PLEKHM1	GABARAPL2	P60520	902
PLEKHM1	ARL8B	Q9NVJ2	894
PLEKHM1	TCIRG1	Q13488	889
PLEKHM1	SNAP29	O95721	888
PLEKHM1	F5GZY7	F5GZY7	857
PLEKHM1	CA2	P00918	777
PLEKHM1	STX17	P56962	754
PLEKHM1	VAMP8	Q9BV40	744
PLEKHM1	TNFRSF11A	Q9Y6Q6	740
PLEKHM1	EPG5	Q9HCE0	737
PLEKHM1	FYCO1	Q9BQS8	732
PLEKHM1	SNX10	Q9Y5X0	730

IntAct

77 interactions, top by confidence:

A	B	Type	Score
PLEKHM1	RAB7A	psi-mi:“MI:0915”(physical association)	0.800
PLEKHM1	RAB7A	psi-mi:“MI:0403”(colocalization)	0.800
RAB7A	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.800
RAB7A	PLEKHM1	psi-mi:“MI:0403”(colocalization)	0.800
VPS41	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.740
PLEKHM1	VPS41	psi-mi:“MI:0914”(association)	0.740
VPS41	VPS11	psi-mi:“MI:0914”(association)	0.710
PLEKHM1	ARL8B	psi-mi:“MI:0915”(physical association)	0.710
PLEKHM1	ARL8B	psi-mi:“MI:0407”(direct interaction)	0.710
ARL8B	PLEKHM1	psi-mi:“MI:0403”(colocalization)	0.710
ARL8B	PLEKHM1	psi-mi:“MI:0407”(direct interaction)	0.710
ARL8B	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.710
RAB7A	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.700
PLEKHM1	RAB7A	psi-mi:“MI:0915”(physical association)	0.700
PLEKHM1	RAB7A	psi-mi:“MI:0403”(colocalization)	0.700

BioGRID (103): PLEKHM1 (Affinity Capture-RNA), PLEKHM1 (Negative Genetic), PLEKHM1 (Affinity Capture-RNA), DEF8 (Affinity Capture-Western), PLEKHM1 (Affinity Capture-Western), KIFC1 (Affinity Capture-Western), TPX2 (Affinity Capture-Western), PLEKHM1 (Affinity Capture-Western), FAM98A (Affinity Capture-Western), NDEL1 (Affinity Capture-Western), MAP3K7 (Affinity Capture-Western), RAP1B (Affinity Capture-Western), PLEKHM1 (Affinity Capture-Western), PLEKHM1 (Affinity Capture-Western), PLEKHM1 (Two-hybrid)

ESM2 similar proteins: A0A140LI67, B5KFD7, D4A7V9, M0R4F8, O08774, O35827, O43187, O70167, O70173, O88866, O88900, O95398, O95704, P0C5Y8, Q0P5I2, Q13322, Q14449, Q4QQS0, Q5BIW4, Q5ICW4, Q5JV73, Q5PQS0, Q5R810, Q60760, Q68DX3, Q6IFT4, Q6IRN0, Q6P4K6, Q6REY9, Q6S5L8, Q6TXD4, Q7TSI1, Q80TQ5, Q80VA5, Q8BW88, Q8CFA1, Q8IWE5, Q8R1C9, Q8R2S1, Q8VCC8

Diamond homologs: A5PJM7, A7E316, O01738, Q08AW4, Q22744, Q3TD16, Q4V8I4, Q5PQS0, Q6DDJ3, Q6DJB3, Q6ZN54, Q6ZWE6, Q7T0P6, Q7TSI1, Q80U62, Q8BM47, Q92622, Q99J78, Q9H714, Q9VTT9, Q9Y4G2, B1AVY7, Q08DX0, Q08E29, Q0V9V7, Q4R7B9, Q559T8, Q5FVJ0, Q5NVC2, Q5R4V2, Q5R5R4, Q5R7A7, Q5U3W3, Q6PDC0, Q7L099, Q80TQ5, Q8BIJ7, Q8IUI4, Q8IWE5, Q8R4C2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
endosome to lysosome transport	6	77.8×	4e-08
protein transport	5	8.4×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

196 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	147
Likely benign	14
Benign	20

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
560304	NM_014798.3(PLEKHM1):c.2140C>T (p.Arg714Cys)	Pathogenic
560305	NM_014798.3(PLEKHM1):c.3053_3054del (p.Thr1018fs)	Pathogenic
922	NM_014798.3(PLEKHM1):c.296+1G>A	Pathogenic
3065942	NM_014798.3(PLEKHM1):c.94C>T (p.Gln32Ter)	Likely pathogenic

SpliceAI

2420 predictions. Top by Δscore:

Variant	Effect	Δscore
17:45439472:CATA:C	donor_loss	1.0000
17:45439473:ATACC:A	donor_loss	1.0000
17:45439474:TACC:T	donor_loss	1.0000
17:45439476:C:A	donor_loss	1.0000
17:45439476:CCTGA:C	donor_gain	1.0000
17:45439634:TCTG:T	acceptor_loss	1.0000
17:45439635:C:CC	acceptor_gain	1.0000
17:45445465:CTCA:C	donor_loss	1.0000
17:45445467:CACCT:C	donor_loss	1.0000
17:45445469:CCT:C	donor_gain	1.0000
17:45445469:CCTCT:C	donor_loss	1.0000
17:45450612:ACTT:A	donor_loss	1.0000
17:45450613:CTT:C	donor_loss	1.0000
17:45450614:TTA:T	donor_loss	1.0000
17:45450615:TA:T	donor_loss	1.0000
17:45450616:A:AC	donor_gain	1.0000
17:45450616:ACCGG:A	donor_loss	1.0000
17:45450617:C:CC	donor_gain	1.0000
17:45450617:C:G	donor_loss	1.0000
17:45450617:CCG:C	donor_gain	1.0000
17:45450617:CCGGG:C	donor_gain	1.0000
17:45453456:T:TA	donor_gain	1.0000
17:45454268:CAGTC:C	acceptor_gain	1.0000
17:45454269:AGTC:A	acceptor_gain	1.0000
17:45454270:GTC:G	acceptor_gain	1.0000
17:45454273:C:CC	acceptor_gain	1.0000
17:45454273:C:G	acceptor_loss	1.0000
17:45454274:T:C	acceptor_loss	1.0000
17:45454280:C:CT	acceptor_gain	1.0000
17:45458203:ATGCC:A	donor_gain	1.0000

AlphaMissense

6875 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:45475461:A:G	W188R	0.999
17:45475461:A:T	W188R	0.999
17:45475662:A:G	W121R	0.999
17:45475662:A:T	W121R	0.999
17:45439535:A:G	C1001R	0.998
17:45439539:G:C	F999L	0.998
17:45439539:G:T	F999L	0.998
17:45439541:A:G	F999L	0.998
17:45450694:C:T	C856Y	0.998
17:45450695:A:G	C856R	0.998
17:45450717:A:C	C848W	0.998
17:45450719:A:G	C848R	0.998
17:45453361:A:G	C831R	0.998
17:45454006:A:G	W616R	0.998
17:45454006:A:T	W616R	0.998
17:45439533:G:C	C1001W	0.997
17:45450686:A:G	C859R	0.997
17:45453359:G:C	C831W	0.997
17:45453360:C:T	C831Y	0.997
17:45453550:A:G	W768R	0.997
17:45453550:A:T	W768R	0.997
17:45477928:A:G	W90R	0.997
17:45477928:A:T	W90R	0.997
17:45439497:A:C	F1013L	0.996
17:45439497:A:T	F1013L	0.996
17:45439499:A:G	F1013L	0.996
17:45439503:G:C	F1011L	0.996
17:45439503:G:T	F1011L	0.996
17:45439505:A:G	F1011L	0.996
17:45439534:C:T	C1001Y	0.996

dbSNP variants (sampled 300 via entrez): RS1000076071 (17:45470330 G>T), RS1000217170 (17:45441969 G>A), RS1000295396 (17:45489850 T>A,C), RS1000302854 (17:45445209 A>C), RS1000325141 (17:45477263 C>G,T), RS1000349429 (17:45439452 G>A,T), RS1000422232 (17:45483223 T>C,G), RS1000600198 (17:45490068 C>A,T), RS1000725400 (17:45458648 T>G), RS1000824119 (17:45452373 T>C), RS1000882896 (17:45434743 G>A,C,T), RS1000906944 (17:45472121 C>T), RS1000932230 (17:45478853 T>C), RS1001069430 (17:45464747 G>C), RS1001082652 (17:45472633 A>G)

Disease associations

OMIM: gene MIM:611466 | disease phenotypes: MIM:611497, MIM:618107, MIM:259700

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive osteopetrosis 6	Strong	Autosomal recessive
osteopetrosis, autosomal dominant 3	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
osteopetrosis, autosomal dominant 3	Limited	AD
autosomal recessive osteopetrosis 6	Moderate	AR

Mondo (4): autosomal recessive osteopetrosis 6 (MONDO:0012679), osteopetrosis, autosomal dominant 3 (MONDO:0020848), bone disorder (MONDO:0005381), autosomal recessive osteopetrosis 1 (MONDO:0009815)

Orphanet (3): Intermediate osteopetrosis (Orphanet:210110), Rare bone disease related to a common gene or pathway defect (Orphanet:364803), Autosomal recessive malignant osteopetrosis (Orphanet:667)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000230	Gingivitis
HP:0000505	Visual impairment
HP:0000689	Dental malocclusion
HP:0000707	Abnormality of the nervous system
HP:0000768	Pectus carinatum
HP:0000843	Hyperparathyroidism
HP:0000938	Osteopenia
HP:0001293	Cranial nerve compression
HP:0001433	Hepatosplenomegaly
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0002240	Hepatomegaly
HP:0002659	Increased susceptibility to fractures
HP:0002684	Thickened calvaria
HP:0002754	Osteomyelitis
HP:0002757	Recurrent fractures
HP:0002901	Hypocalcemia
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003418	Back pain
HP:0004348	Abnormality of bone mineral density
HP:0004618	Sandwich appearance of vertebral bodies
HP:0004975	Erlenmeyer flask deformity of the femurs
HP:0005652	Cortical sclerosis
HP:0005746	Osteosclerosis of the base of the skull
HP:0005789	Generalized osteosclerosis
HP:0006480	Premature loss of teeth

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000567_1	Parkinson’s disease	6.000000e-08
GCST002748_11	Epithelial ovarian cancer	2.000000e-13
GCST004077_10	Cognitive function	6.000000e-07
GCST005116_48	Male-pattern baldness	1.000000e-24
GCST005116_49	Male-pattern baldness	1.000000e-26
GCST005116_50	Male-pattern baldness	3.000000e-16
GCST005232_131	Neuroticism	8.000000e-26
GCST005835_6	Remission after SSRI treatment in MDD or neuroticism	3.000000e-11
GCST006661_255	Male-pattern baldness	2.000000e-22
GCST006661_281	Male-pattern baldness	8.000000e-29
GCST006716_14	Alcohol use disorder (total score)	5.000000e-10
GCST008162_112	Hip circumference	7.000000e-06
GCST010703_91	Brain morphology (MOSTest)	2.000000e-65
GCST011494_74	Daytime nap	1.000000e-72
GCST011616_5	Cortical volume	8.000000e-13
GCST90002393_524	Monocyte count	9.000000e-21
GCST90013406_208	Liver enzyme levels (alkaline phosphatase)	2.000000e-17

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0007660	neuroticism measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0009458	alcohol use disorder measurement
EFO:0004346	neuroimaging measurement
EFO:0007828	daytime rest measurement
EFO:0005091	monocyte count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001847	Bone Diseases	C05.116
C564915	Osteopetrosis, Autosomal Recessive 1 (supp.)
C566931	Osteopetrosis, Autosomal Recessive 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression, affects cotreatment	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Ozone	affects expression, increases abundance, decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases abundance, increases expression	1
diethyl maleate	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzene	increases expression	1
Folic Acid	decreases expression	1
Phthalic Acids	increases methylation	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vanadates	decreases expression	1
Cyclosporine	increases expression	1

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01166854	Not specified	RECRUITING	Characterization of Familial Myopathy and Paget Disease of Bone
NCT03527511	Not specified	COMPLETED	Effect of Active Vitamin D and Etelcalcetide on Human Osteoclasts in Patients With Chronic Kidney Disease
NCT06444503	Not specified	RECRUITING	Clinico-biological Collection of Bone, Calcium and Growth Plate Pathologies